Background:The traditional Chinese medicine Toosendan Fructus has certain hepatotoxicity,which is used after being processed by stir-frying to attenuate toxicity.However,there are few studies on its attenuating toxici...Background:The traditional Chinese medicine Toosendan Fructus has certain hepatotoxicity,which is used after being processed by stir-frying to attenuate toxicity.However,there are few studies on its attenuating toxicity mechanism.The effects of Toosendan Fructus on the activities of CYP450P1A2,CYP2E1 and CYP3A4 were studied in vivo and in vitro and the dose-toxicity mechanism of hepatotoxicity before and after stir-frying was explored to provide the basis for safe,rational use of Toosendan Fructus.Methods:The rat liver microsomes in vitro incubation method and in vivo pharmacokinetics were used to detect the concentrations of phenacetin,chlorzoxazone and dapsone in the liver microsomes in vitro incubation system and the rat plasma to study the effect of stir-frying of Toosendan Fructus on the activity of CYP450P1A2,CYP2E1,CYP3A4.Results:The results of pharmacokinetics in vivo showed that the AUC of phenacetin and dapsone in different groups was lower,and CL value was higher than those of the normal group.At the same dose,the AUC of stir-fried Toosendan Fructus was higher than that of the raw,while CL value was lower.For the same processed product,AUC value was high-dose>low-dose>middle-dose group,CL value was high-dose<low-dose<middle-dose.AUC and CL values of chlorzoxazone showed no difference from those of the normal group.The results of pharmacokinetics in vivo showed that Toosendan Fructus can induce the activity of CYP3A4 in a dose-dependent manner and the induction effect will decrease after stir-frying in vitro.Conclusion:The toxicity attenuation of Toosendan Fructus may be related to the decrease of induction effect after stir-frying.These results would provide the basis for safe,rational use of Toosendan Fructus.展开更多
Objective:Objective:To analyze and explore the key targets and molecular mechanisms of action of Radix Paeoniae Alba against Toosendan Fructus-induced hepatotoxicity and the relationship between corresponding compound...Objective:Objective:To analyze and explore the key targets and molecular mechanisms of action of Radix Paeoniae Alba against Toosendan Fructus-induced hepatotoxicity and the relationship between corresponding compounds based on network pharmacology.Methods:Using network pharmacology,a"traditional Chinese medicine-chemical composition-key target-pathway"analysis was conducted on Radix Paeoniae Alba for the treatment of Toosendan Fructus-induced hepatotoxicity.The possible mechanism of action was analyzed in terms of function.Results:The core targets,such as interleukin(IL)-6,tumor necrosis factor(TNF),heat shock protein 90 alpha family class A member 1(HSP90AA1),peroxisome proliferator-activated receptor gamma(PPARG),prostaglandin-endoperoxide synthase 2(PTGS2),heme oxygenase 1(HMOX1),Jun proto-oncogene(JUN),caspase-3,estrogen receptor 1(ESR1),and aryl hydrocarbon receptor(AHR)were screened from the targets of Radix Paeoniae Alba against Toosendan Fructus-induced hepatotoxicity.Biological process(BP)of toxic targets(BP terms)involved"response to drug;activation of cysteine-type endopeptidase activity involved in apoptotic process,”positive regulation of transcription.Cellular components(CC terms)mainly involved cytosol and membrane rafts.Molecular function(MF)terms included"protein homodimerization activity,"RNA polymerase II transcription factor activity and enzyme binding,etc."The Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway included the TNF signaling pathway,cancer pathways,and apoptosis.Conclusion:Radix Paeoniae Alba might alleviate Toosendan Fructus-induced hepatotoxicity through IL6,TNF,HSP90AA1,PPARG,PTGS2,HMOX1,and other targets,possibly via the activation of cysteine-type endopeptidase activity involved in these pathways.展开更多
Objective:To explore the potential mechanism of hepatotoxicity induced by Fructus Meliae Toosendan(FMT)through network pharmacology.Methods:The active components and targets of FMT were identified and screened by Trad...Objective:To explore the potential mechanism of hepatotoxicity induced by Fructus Meliae Toosendan(FMT)through network pharmacology.Methods:The active components and targets of FMT were identified and screened by Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform Database,PubChem Database and Swiss Target Prediction database,etc.Genecards,pharmGKB,and OMIM databases were used to collect relevant targets of hepatotoxicity,and intersect them with the targets of active ingredients to obtain the potential targets of hepatotoxicity caused by FMT.A compound-target network was constructed with Cytoscape 3.8.0 software.The String 11.0 database was used to construct the protein-protein interaction(PPI)network of the targets and to screen out the core targets.In addition,Gene Ontology(GO)terms and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analyses were conducted by R software,and then the pathways directly related to hepatotoxicity were integrated.Results:In this study,9 active ingredients of FMT and 265 targets were obtained.There are 533 hepatotoxicity-related targets,and 76 potential targets for hepatotoxicity caused by FMT,among which quercetin,melianone,and nimbolin A are the key active components for hepatotoxicity caused by FMT,and MYC,STAT3,JUN,and RELA were the core target proteins of FMT’s hepatotoxicity.There were 2353 GO entries(P<0.05),including 2181 Biological Process(BP),41 Cellular Component(CC)and 131 Molecular Function(MF).KEGG enrichment analysis revealed 165 pathways(P<0.05),of which Th17 cell differentiation,HIF-1 signaling pathway,PI3K-Akt signaling pathway were strongly correlated with the hepatotoxicity of FMT.Conclusion:Through network pharmacology,it was found that many potential components in azadirachia chinaberry may be involved in the regulation of apoptosis,excessive inflammatory response and mitochondrial dynamics through multi-target and multi-pathway,resulting in the generation of hepatotoxicity.展开更多
基金supported by Natural Key R&D Program of China(No.2018YFC1707000).
文摘Background:The traditional Chinese medicine Toosendan Fructus has certain hepatotoxicity,which is used after being processed by stir-frying to attenuate toxicity.However,there are few studies on its attenuating toxicity mechanism.The effects of Toosendan Fructus on the activities of CYP450P1A2,CYP2E1 and CYP3A4 were studied in vivo and in vitro and the dose-toxicity mechanism of hepatotoxicity before and after stir-frying was explored to provide the basis for safe,rational use of Toosendan Fructus.Methods:The rat liver microsomes in vitro incubation method and in vivo pharmacokinetics were used to detect the concentrations of phenacetin,chlorzoxazone and dapsone in the liver microsomes in vitro incubation system and the rat plasma to study the effect of stir-frying of Toosendan Fructus on the activity of CYP450P1A2,CYP2E1,CYP3A4.Results:The results of pharmacokinetics in vivo showed that the AUC of phenacetin and dapsone in different groups was lower,and CL value was higher than those of the normal group.At the same dose,the AUC of stir-fried Toosendan Fructus was higher than that of the raw,while CL value was lower.For the same processed product,AUC value was high-dose>low-dose>middle-dose group,CL value was high-dose<low-dose<middle-dose.AUC and CL values of chlorzoxazone showed no difference from those of the normal group.The results of pharmacokinetics in vivo showed that Toosendan Fructus can induce the activity of CYP3A4 in a dose-dependent manner and the induction effect will decrease after stir-frying in vitro.Conclusion:The toxicity attenuation of Toosendan Fructus may be related to the decrease of induction effect after stir-frying.These results would provide the basis for safe,rational use of Toosendan Fructus.
文摘Objective:Objective:To analyze and explore the key targets and molecular mechanisms of action of Radix Paeoniae Alba against Toosendan Fructus-induced hepatotoxicity and the relationship between corresponding compounds based on network pharmacology.Methods:Using network pharmacology,a"traditional Chinese medicine-chemical composition-key target-pathway"analysis was conducted on Radix Paeoniae Alba for the treatment of Toosendan Fructus-induced hepatotoxicity.The possible mechanism of action was analyzed in terms of function.Results:The core targets,such as interleukin(IL)-6,tumor necrosis factor(TNF),heat shock protein 90 alpha family class A member 1(HSP90AA1),peroxisome proliferator-activated receptor gamma(PPARG),prostaglandin-endoperoxide synthase 2(PTGS2),heme oxygenase 1(HMOX1),Jun proto-oncogene(JUN),caspase-3,estrogen receptor 1(ESR1),and aryl hydrocarbon receptor(AHR)were screened from the targets of Radix Paeoniae Alba against Toosendan Fructus-induced hepatotoxicity.Biological process(BP)of toxic targets(BP terms)involved"response to drug;activation of cysteine-type endopeptidase activity involved in apoptotic process,”positive regulation of transcription.Cellular components(CC terms)mainly involved cytosol and membrane rafts.Molecular function(MF)terms included"protein homodimerization activity,"RNA polymerase II transcription factor activity and enzyme binding,etc."The Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway included the TNF signaling pathway,cancer pathways,and apoptosis.Conclusion:Radix Paeoniae Alba might alleviate Toosendan Fructus-induced hepatotoxicity through IL6,TNF,HSP90AA1,PPARG,PTGS2,HMOX1,and other targets,possibly via the activation of cysteine-type endopeptidase activity involved in these pathways.
基金Project supported by Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital,(No.202016)。
文摘Objective:To explore the potential mechanism of hepatotoxicity induced by Fructus Meliae Toosendan(FMT)through network pharmacology.Methods:The active components and targets of FMT were identified and screened by Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform Database,PubChem Database and Swiss Target Prediction database,etc.Genecards,pharmGKB,and OMIM databases were used to collect relevant targets of hepatotoxicity,and intersect them with the targets of active ingredients to obtain the potential targets of hepatotoxicity caused by FMT.A compound-target network was constructed with Cytoscape 3.8.0 software.The String 11.0 database was used to construct the protein-protein interaction(PPI)network of the targets and to screen out the core targets.In addition,Gene Ontology(GO)terms and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analyses were conducted by R software,and then the pathways directly related to hepatotoxicity were integrated.Results:In this study,9 active ingredients of FMT and 265 targets were obtained.There are 533 hepatotoxicity-related targets,and 76 potential targets for hepatotoxicity caused by FMT,among which quercetin,melianone,and nimbolin A are the key active components for hepatotoxicity caused by FMT,and MYC,STAT3,JUN,and RELA were the core target proteins of FMT’s hepatotoxicity.There were 2353 GO entries(P<0.05),including 2181 Biological Process(BP),41 Cellular Component(CC)and 131 Molecular Function(MF).KEGG enrichment analysis revealed 165 pathways(P<0.05),of which Th17 cell differentiation,HIF-1 signaling pathway,PI3K-Akt signaling pathway were strongly correlated with the hepatotoxicity of FMT.Conclusion:Through network pharmacology,it was found that many potential components in azadirachia chinaberry may be involved in the regulation of apoptosis,excessive inflammatory response and mitochondrial dynamics through multi-target and multi-pathway,resulting in the generation of hepatotoxicity.
